This is the fourth competitive renewal of this grant application that was funded for the past 20 years. Over the years funding through this grant application led to several milestone observations and new discoveries. In the current grant application, we will follow intriguing observations made during the last period of funding. Our genetic studies in mice, using systemic deletion of Akt isoforms after tumor onset, recapitulate some of the adverse effects observed in patients after treatment with PI3K and Akt inhibitors such as hyperinsulinemia, and hyperglycemia, severe diarrhea, and liver damage. Our studies in mice could therefore provide mechanistic explanations for the adverse physiological consequences induced by PI3K and Akt inhibitors. Our results using mouse models of breast cancer and inducible systemic deletion of Akt isoforms after tumor onset to emulate drug therapy, suggest the followings: (i) Systemic Akt1 inhibition after tumor onset reduces metastasis by inhibiting tumor associate and pro-metastatic neutrophils. This is relevant to human breast cancer as high ratio of neutrophils to lymphocyte (NLR) is associated with worse overall survival and disease-free survival. (ii) Neutrophils’ specific deletion of Akt1 is sufficient to inhibit breast cancer metastasis. (iii) Specific Akt1 inhibitors could inhibit tumor progression and metastasis of Her2 enriched, Luminal B, and triple negative breast cancer. (iv) Systemic Akt1 inhibition prohibits breast cancer metastasis regardless of primary tumor type (Akt1 specific inhibitors should be developed). (v) Systemic Akt2 inhibition may not be beneficial for breast cancer therapy because of increased circulating levels of insulin and hyperactivation of the other Akt isoforms (drugs that inhibit Akt2 might be avoided). (vi) Pan-Akt inhibitors may not be effective unless they don’t inhibit Akt2 activity to a high extent. In the first part of the current grant application, we will investigate how tumor associated neutrophils are programmed by the tumors both transcriptionally and metabolically and how Akt1 deficiency impairs their ability to promote breast cancer metastasis. In the second part of the grant application will investigate mechanistically the adverse effects induced by pan-Akt or Akt2 inhibition and how to alleviate them. The long-term goal of this grant application is to establish the rationale for developing Akt1 specific inhibitors and enable the efficient use of Akt inhibitors for cancer and cancer metastasis therapy.

The PI3K/Akt signaling is frequently hyperactivated in cancer. However, targeting this pathway is often associated with adverse effects, which either prohibit further treatment or decrease the efficacy of Akt inhibition. The goal of this grant application is to find ways to inhibit Akt effectively for the therapy of cancer and cancer metastasis, and to mitigate adverse consequences.